ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms

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1 Consensus Guidelines Published online: January 5, 2016 Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms J.K. Ramage a W.W. De Herder b G. Delle Fave c P. Ferolla d D. Ferone e T. Ito f P. Ruszniewski g A. Sundin h W. Weber i Z. Zheng-Pei j B. Taal k A. Pascher l all other Vienna Consensus Conference participants a Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire, UK; b Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands; c Department of Digestive and Liver Disease, Ospedale Sant Andrea, Rome, d NET Centre, Umbria Regional Cancer Network, Università degli Studi di Perugia, Perugia, and e Department of Endocrine and Metabolic Sciences (DIMI), University of Genoa, Genoa, Italy; f Pancreatic Diseases Branch, Kyushu University Hospital, Fukuoka, Japan; g Department of Gastroenterology, Beaujon Hospital, Clichy, France; h Department of Radiology, Section for Molecular Imaging, University Hospital, Uppsala, Sweden; i Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, N.Y., USA; j Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China; k Netherlands Cancer Centre, Lijnden, The Netherlands; l Department of Visceral and Transplant Surgery, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany Introduction A more extensive paper on colorectal neuroendocrine neoplasms (NENs) is provided in the 2012 Guidelines, additional information over the past 2 years and/or expert opinions have thus been incorporated into this guideline update. Epidemiology It is becoming clearer that rectal NEN is a different disease to colonic NEN. Rectal NENs are commonly (but not exclusively) small and generally low to intermediate grade [grades 1 or 2 (G1 or G2)], whereas colonic NENs are often aggressive, poorly differentiated and higher grade (G3). Rectal NENs have become more frequent than small intestine neuroendocrine tumors (NETs) since karger@karger.com S. Karger AG, Basel /16/ $39.50/0 There are some differences between the USA and Korea as demonstrated by publications from Taghavi et al. [1] and Jung et al. [2] : 1 Rectal NETs are more common in women in a US population (OR 1.196); however, they more likely in men in Korea (OR 1.92). In the USA, the highest incidence was in Asians (OR 10) and Blacks (OR 1.96), confirmed by a paper from Taghavi et al. [1] ; a new finding is the high incidence in Hispanics (OR 2.6). 2 The report by Yangong et al. showed that ulceration occurs in tumors >2 cm [3] (in 284 cases with tumors <2 cm vs. in 28 cases with tumors >2 cm). 3 In a single-center retrospective series from Baltimore, Md., USA [4], no metastases were seen in lesions 9 mm, and this follows the previous recommendations guiding investigations, outcomes and thera- For an alphabetical list of all other Vienna Consensus Conference participants, see Appendix. Prof. John K. Ramage North Hampshire Hospital Aldermaston Road Basingstoke RG24 9NA (UK) doctors.org.uk

2 140 peutic options based on cut-off sizes of 10 and 20 mm. The occurrence of multiple rectal NENs was also noted by Park et al. [5] who recommended full colonoscopy in the presence of one colorectal NEN. Screening Colonoscopy screening programs are picking up NENs of the colon and terminal ileum. The incidence rate at screening is 0.17% [2]. They appear as yellowish polypoids or flat doughnut-shaped lesions, but there may be central ulceration. Ideally, lesions should be tattooed at the time of removal if thought to be a NET, since further therapy may be needed. A referral should be made to NET MDM/tumor board for further management. The incidence of rectal NET is positively associated with young age, male gender, alcohol and LDL levels. Predictors of Outcome Factors predicting lymph node involvement and metastasis continue to be examined, in view of uncertainty over whether recurrence is likely to occur in resected colorectal NENs. Al Natour et al. [6] examined the SEER data of 929 patients with localized colonic NEN which were all treated surgically. They found that tumor size and depth predicted lymph node metastasis and showed that intramucosal tumors <1 cm have a 4% risk of lymph node metastasis. Tumors <10 mm had a 3% risk of metastasis in the Baltimore group [4], and while the risk is not zero for small tumors, the majority of patients appear cured once full s of small (<10 mm) rectal NENs with favorable biology are performed. Predictors of survival were further examined by Weinstock et al. [7] who showed that stage was the strongest predictor of survival in multivariate analysis and that grade, size, symptoms and treatment modality were only significant in univariate analysis. In this study, discrimination of size as a predictor was confirmed between <1 and >1 cm, but no discrimination was seen with regard to prognosis between 1 and 2 versus >2 cm in size. This group also found a small risk of metastasis in tumors <1 cm (1%), and the majority of tumors >2 cm had metastasized (60%) [7]. Size of the primary, therefore, remains a less than totally reliable discriminator of prognosis. When examining high-grade neuroendocrine carcinomas in 126 patients, Smith et al. [8] suggested that a more favorable prognosis may be present if there is an adenocarcinoma component on histology. Classification With regard to prediction of short-term prognosis, the WHO 2010 classification was found to be superior to the WHO 2000 classification by Lee et al. [9] ; and the staging system was validated by survival analysis [7]. Therapy ( fig. 1 ) Endoscopy and Surgery Endoscopic of rectal tumors can be by: simple polypectomy, endoscopic mucosal (EMR) with modified EMR band ligation, endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEMS). For lesions <10 mm and no involvement of the muscularis propria, EMR is adequate once complete, but EMR band-assisted ligation may improve the number of complete s [10]. If EMR results in an incomplete, then ESD or TEMS may be indicated as salvage therapy; these data came from inferences within citations, as there are no actual recurrences in this situation. It is not clear from the literature whether rescue or salvage therapies are really required and if so, which of these is the best option, but TEMS leads to more complications [10 12]. Patients with an incomplete from snare polypectomy (this technique is not recommended), EMR or other techniques should be discussed on a case-per-case basis at centers of excellence in treating NEN. Endoscopic ultrasound is recommended for most rectal NENs except perhaps for very small (<5 mm) lesions that have been completely removed where it may not be necessary. Determining the cut-off size has also been challenged by recent data. As minimally invasive procedures gather momentum and improve in completeness of excision, cut-off sizes may need to be revised. In the series by Gleeson et al. [4], no metastases were seen in lesions 9 mm, and local was deemed safe in lesions between 10 and 16 mm according to McDermott et al. [13] (this was, however, a pooled analysis with data quality scoring low/moderate for all series included). In the series of rectal lesions by Yangong et al. [3], no recurrence was seen in 248 cases after transanal and endoscopic polypectomy. Similarly, Shigeta et al. [14] questioned whether radical is better than local for rectal carcinoids for tumor sizes mm with and without positive lymph nodes and found that radical surgery reduces quality of life. Although these series are reassuring that recurrence is uncommon, further evidence is needed to conclude that local is safe for these intermediate tumors. Ramage et al.

3 (May be completely removed in polyp at endoscopy) <1 cm T1 (G1/G2) T2 (G1/G2) Endoscopic Complete local G1: 6 months follow-up + consider repeat G2: complete local Consider TME Other (rare): - G3 ± metastasis - Metastatic disease Rectal NETs at endoscopy EUS - Anorectal EUS - Pelvic MRI As appropriate: - CT/MRI chest/abdomen - Colonoscopy - Octreoscan/somatostatin receptor imaging/fdg PET (if high grade) 1 2 cm (G1/G2) 1 2 cm (G3) >2 cm (G1 G3) MRI/CT MRI/CT/SRS/PET T1 (G1/G2) T2 (G1 3) Without metastasis With metastasis/pos. Complete local Anterior /TME Anterior /TME Obstruction/ bleeding No obstruction/ bleeding Repeat /TME If N1 G2 T4 or G3 consider adjuvant systemic therapy If N1 G2 T4 or G3 consider adjuvant systemic therapy Palliative / stent/chemotherapy Chemotherapy/Rx Fig. 1. Algorithm for treating rectal NETs. Smith et al. [8] provided evidence that of the primary in high-grade colorectal NENs with or without metastases does not result in improved prognosis (median survival 13 months). This is in contrast to adenocarcinoma and is more in keeping with small cell lung cancer in terms of prognosis and outcomes of surgery. A smaller study by Aytac et al. [15] confirmed these findings and introduced the issue of radiotherapy for rectal high-grade neuroendocrine carcinoma, but without conclusive evidence of benefit. The combination of everolimus and octreotide has been reported in the RADIANT-2 trial [16]. In a post-hoc analysis, there was improved progression-free survival compared to placebo in the RADIANT-2 study; there may, therefore, be some rationale for using this combination in well-differentiated G1/G2 colorectal NENs, but this remains to be verified [17]. Similarly, the use of somatostatin analogues somatuline autogel was tested in a phase III study (CLARINET study), but as there were only 14 cases of colorectal NENs, it is impossible to predict real benefit (even in patients with overexpression of somatostatin receptors). Summary There are some changes to the 2011 Guidelines as a result of some large series clarifying the risk of recurrence and introducing different methods of therapy in these tumors which are increasingly common. It is important that clinicians throughout the wide ranges of disciplines treating these cases are aware of these updates. Please also refer to the consensus guideline updates for other gastroenteropancreatic neuroendocrine tumors [ 18 23, this issue]. Appendix All Other Vienna Consensus Conference Participants Anlauf, M. (Institut für Pathologie und Zytologie, St. Vincenz Krankenhaus, Limburg, Germany); Bartsch, D.K. (Department of Surgery, Philipps University, Marburg, Germany); Baudin, E. (Institut Gustave Roussy, Villejuif, France); Capdevila, J. (Institute of Oncology, Vall d Hebron University Hospital, Barcelona, Spain); Caplin, M. (Neuroendocrine Tumour Unit, Royal Free Hospital, Consensus Guidelines Update for Colorectal NEN 141

4 London, UK); Costa, F. (Centro de Oncologia, Hospital Sírio Libanês, São Paulo, Brazil); Cwikla, J.B. (Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland); Eriksson, B. (Department of Endocrine Oncology, University Hospital, Uppsala, Sweden); Falconi, M. (Department of Surgery, San Raffaele Hospital, Università Vita e Salute, Milan, Italy); Garcia-Carbonero, R. (Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain); Gross, D. (Department of Endocrinology and Metabolism, Hadassah University Hospital, Mevasseret Tsion, Israel); Jensen, R.T. (Digestive Diseases Branch, NIH, Bethesda, Md., USA); Kaltsas, G. (Department of Pathophysiology, Divison of Endocrinology, National University of Athens, Athens, Greece); Kelestimur, F. (Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey); Kianmanesh, R. (Department of Surgery, CHU Robert Debré, Reims, France); Klöppel, G. (Institute of Pathology, Technische Universität München, Munich, Germany); Knigge, U. (Neuroendocrine Tumor Center of Excellence, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark); Kos- Kudla, B. (Department of Endocrinology, Medical University of Silesia, Katowice, Poland); Krenning, E. (Department of Internal Medicine, Division of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands); Kwekkeboom, D. (Department of Internal Medicine, Division of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands); Niederle, B. (Department of Surgery, Medical University of Vienna, Vienna, Austria); Öberg, K. (Department of Medical Sciences, Endocrine Oncology Unit, University Hospital, Uppsala, Sweden); O Connor, J. (Department of Clinical Oncology, Institute Alexander Fleming, Buenos Aires, Argentina); O Toole, D. (NET Centre, St. Vincent s University and Department of Clinical Medicine, St. James Hospital and Trinity College, Dublin, Ireland); Pape, U.-F. (Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany); Pavel, M. (Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany); Perren, A. (Institute of Pathology, University of Bern, Bern, Switzerland); Raymond, E. (Oncologie Médicale, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France); Reed, N. (Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, UK); Rindi, G. (Institute of Anatomic Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy); Sedlackova, E. (Department of Oncology, First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic); Sorbye, H. (Department of Oncology, Haukeland University Hospital, Bergen, Norway); Toumpanakis, C. (Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK); Wiedenmann, B. (Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin, Germany). References 1 Taghavi S, Jayarajan SN, Powers BD, Davey A, Willis AI: Examining rectal carcinoids in the era of screening colonoscopy: a surveillance, epidemiology, and end results analysis. Dis Colon Rectum 2013; 56: Jung KS, Yun KE, Chang Y, Ryu S, Park JH, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Park DI: Risk factors associated with rectal neuroendocrine tumors: a cross-sectional study. Cancer Epidemiol Biomarkers Prev 2014; 23: Yangong H, Shi C, Shahbaz M, Zhengchuan N, Wang J, Liang B, Ruliang F, Gao H, Bo Q, Niu J: Diagnosis and treatment experience of rectal carcinoid (a report of 312 cases). Int J Surg 2014; 12: Gleeson F, Levy ML, Dozois EJ, Larson DW, Song L, Boardman LA: Endoscopically identified well-differentiated rectal carcinoid tumors: impact of tumor size on the natural history and outcomes. Gastrointest Endoscopy 2014; 80: Park CS, Lee SH, Kim SB, Kim KO, Jang BI: Multiple rectal neuroendocrine tumors: report of five cases. Korean J Gastroenterol 2014; 64/2: Al Natour RH, Saund MS, Sanchez VM, Whang EE, Sharma AM, Huang Q, Boosalis VA, Gold JS: Tumor size and depth predict rate of lymph node metastasis in colon carcinoids and can be used to select patients for endoscopic. J Gastrointest Surg 2012; 16: Weinstock B, Ward SC, Harpaz N, Warner RR, Itzkowitz S, Kim MK: Clinical and prognostic features of rectal neuroendocrine tumors. Neuroendocrinology 2013; 98: Smith JD, Reidy DL, Goodman KA, Shia J, Nash GM: A retrospective review of 126 highgrade neuroendocrine carcinomas of the colon and rectum. Ann Surg Oncol 2014; 21: Lee JL, Yu CS, Kim M, Hong SM, Lim SB, Kim JC: Prognostic impact of diagnosing colorectal neuroendocrine carcinoma using the World Health Organization 2010 classification. Surgery 2014; 155: Lee SH, Park SJ, Kim HH, Ok KS, Kim JH, Jee SR, Seol SY, Kim BM: Endoscopic for rectal carcinoid tumors: comparison of polypectomy and endoscopic submucosal with band ligation. Clin Endosc 2012; 45: Jeon JH, Cheung DY, Lee SJ, Kim HJ, Kim HK, Cho HJ, Lee IK, Kim JI, Park SH, Kim JK: Endoscopic yields reliable outcomes for small rectal neuroendocrine tumors. Dig Endosc 2014; 26: Wu J, Srirajaskanthan R, Ramage J: Rectal neuroendocrine tumor. Dig Endosc 2014; 26: McDermott FD, Heeney A, Courtney D, Mohan H, Winter D: Rectal carcinoids: a systematic review. Surg Endosc 2014; 28: Shigeta K, Okabayashi K, Hasegawa H, Ishii Y, Ochiai H, Tsuruta M, Mukai M, Kameyama K, Uraoka T, Yahagi N, Kitagawa Y: Longterm outcome of patients with locally resected high- and low-risk rectal carcinoid tumors. J Gastrointest Surg 2014; 18: Aytac E, Ozdemir Y, Ozuner G: Long term outcomes of neuroendocrine carcinomas (high-grade neuroendocrine tumors) of the colon, rectum, and anal canal. J Visc Surg 2014; 151: Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group: Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378: Castellano D, Bajetta E, Panneerselvam A, Saletan S, Kocha W, O Dorisio T, Anthony LB, Hobday T; RADIANT-2 Study Group: Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study. Oncologist 2013; 18: Ramage et al.

5 18 Delle Fave G, O Toole D, Sundin A, Taal B, Ferolla P, Ramage JK, Ferone D, Ito T, Weber W, Zheng-Pei Z, De Herder WW, Pascher A, Ruszniewski P; all other Vienna Consensus Conference participants: consensus guidelines update for gastroduodenal neuroendocrine neoplasms. Neuroendocrinology 2016; 103: Niederle B, Pape UF, Costa F, Gross D, Kelestimur F, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O Connor J, O Toole D, Krenning E, Reed N, Kianmanesh R; all other consensus guidelines update for neuroendocrine neoplasm of the jejunum and ileum. Neuroendocrinology 2016; 103: Pape UF, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, Knigge U, Öberg K, Pavel M, Perren A, Toumpanakis C, O Connor J, Krenning E, Reed N, O Toole D; all other consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology 2016; 103: Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, Kos-Kudla B, Kwekkeboom D, Rindi G, Klöppel G, Reed N, Kianmanesh R, Jensen RT; all other Vienna Consensus Conference participants: consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016; 103: Pavel M, O Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape UF, Öberg K; all other consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016; 103: Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M, Cwikla JB, Caplin M, O Toole D, Perren A; all other consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 2016; 103: Consensus Guidelines Update for Colorectal NEN 143

Consensus guidelines update for colorectal neuroendocrine

Consensus guidelines update for colorectal neuroendocrine Neuroendocrinology (DOI:10.1159/000443166) (Accepted, unedited article not yet assigned to an issue) Advanced Release: January 5, 2016 2016 S. Karger AG, Basel www.karger.com/nen Received: Accepted after